Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
Carmen Herranz, Francesca Mateo, Alexandra Baiges, Gorka Ruíz de Garibay, Alexandra Junza, Simon R. Johnson, S. Miller, Nadia García, Jordi Capellades, Antonio Gómez, August Vidal, Luís Palomero, Roderic Espín, Ana I. Extremera, Eline Blommaert, Eva Revilla‐López, Berta Sáez, Susana Gómez‐Ollés, Julio Ancochea, Claudia Valenzuela, Tamara Alonso, Piedad Ussetti, Rosalía Laporta, Antoni Xaubet, José Antonio Rodríguez-Portal, Ana Montes‐Worboys, Carlos Machahua, Jaume Bordas-Martínez, Javier A. Menéndez, Josep M. Cruzado, Roser Guiteras, Christophe Bontoux, Concettina La Motta, Aleix Noguera‐Castells, Mario Mancino, Enrique Lastra, Raül Rigo‐Bonnin, José C. Perales, Francesc Viñals, Álvaro Lahiguera, Xiaohu Zhang, Daniel Cuadras, Coline H.M. van Moorsel, Joanne J. van der Vis, Marian J.R. Quanjel, Harilaos Filippakis, Razqallah Hakem, Chiara Gorrini, Marc Ferrer, Aslihan Ugun‐Klusek, E. Ellen Billett, Elżbieta Radzikowska, Álvaro Casanova, María Molina‐Molina, Antonio Román, Óscar Yanes, Miguel Ángel Pujana
Abstract
Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.